Abstract: Ample evidence from animal and human studies demonstrate that HIV infects the brain during acute stage of the disease, setting the stage for inflammatory responses culminating in a clinical manifestation of HIV-Associated Neurocognitive Disorders (HAND). It is unknown whether long lived-infected brain cells release productive virus that can egress from the brain to re-seed peripheral organs. Astrocytes are the predominate cell type in the brain and while they resist HIV fusion, they can support HIV entry though alternative mechanisms, and HIV integration and re-activation of latent HIV. Given the inability for invasive studies to examine the role of the CNS in general and astrocytes in particular as a reservoir for HIV in humans and its dynamic interaction with peripheral organs, we developed a chimeric human astrocyte/human peripheral blood mononuclear cell mouse model to address the role of astrocytes in harboring replication competent HIV and in dissipating HIV from the brain to the periphery. We demonstrate astrocyte-initiated replication competent HIV spread from the brain to the spleen and lymph nodes. In this application, we propose to determine the mechanism by which HIV egress from the brain to peripheral organs (Aim 1), evaluate HIV egress from HIV infected astrocytes to peripheral organs under combination antiretroviral therapy (cART) (Aim 2), and assess viral evolution within the brain and between the brain and peripheral organs over time (Aim 3). Collectively our studies will establish a paradigm shift and a greater understanding of the dynamic interaction of HIV between the brain and peripheral organs, which can inform novel CNS-targeted therapeutic interventions.